Many organisms synthesize proteins (or peptides) which are degraded to relatively small hydrophobic or amphipathic, bioactive peptides. These peptides exhibit antibiotic, fungicidal, virucidal, hemolytic and/or tumoricidal activities by interacting with membranes and forming transmembrane channels that allow the free flow of electrolytes, metabolites and water across the phospholipid bilayers. Most of these peptides appear to function in biological warfare. There are many designations given to these bioactive peptides. They include the magainins, cecropins, melittins, defensins, bacteriocidins, etc. Certain common structural features observed between members of distinct families suggest that at least some of these families share a common ancestry. The process of pore formation for mellitin in lipid bilayers has been studied in some detail (Lee et al. 2013). Melittin (26 residues) is possibly the best studied of the insect peptide toxins. It is found in the venom of the European honey bee, Apis mellifera. Three-dimensional structures of melittin have been elucidated. The ohmic behavior of melittin is explained by
the persistence of the peptide orientation initially assumed at trans-negative potentials, even after
application of trans-positive ones (Becucci et al. 2016). The interactions of melittin with the outer and cytoplasmic membranes of live E. coli cells has been studied (Yang et al. 2018).

Time-dependent pore formation has been studied in individual giant unilamellar vesicles exposed to a melittin solution (Lee et al., 2008). An individual vescile first expanded its surface area at constant volume and then suddenly reversed expansion of its volume at constant area. The area expansion, the volume expansion, and the point of reversal all matched the results of equilibrium measurements performed on peptide-lipid mixtures. The mechanism includes negative feedback that makes peptide-induced pores stable with a well defined size. Melittin creates transient pores in lipid bilayers (Santo et al. 2013; Wiedman et al. 2013). It and its derivatives penetrate and form water channels in bacterial and mammalian cell membranes (Wu et al. 2016). The energetics of the process involving addition of melittin to a membrane of known composition to form a transmembrane pore have been estimated (Lyu et al. 2017).

Sengupta et al. (2008) used molecular dynamics simulation
to study the interaction of a specific class of
melittin with a dipalmitoylphosphatidylcholine bilayer. Transmembrane pores spontaneously formed above a
critical peptide to lipid ratio. The lipid molecules bent inwards to
form a toroidally shaped pore but with only one or two peptides lining
the pore, in contrast to the traditional models of
toroidal pores in which the peptides are assumed to adopt a
transmembrane orientation. Sengupta et al., 2008 reported that peptide aggregation, either
prior to or after binding to the membrane surface, is a prerequisite for
pore formation, but that the presence of a stable helical secondary structure of
the peptide is not. Electrostatic interactions are important
in the poration process; removing charges of the basic amino-acid
residues of melittin prevents pore formation. In
the absence of counter ions, pores not only form more rapidly, but lead
to membrane rupture via a novel recursive
poration pathway.

A 9-mus all-atom molecular-dynamics simulation
starting from a closely packed transmembrane melittin tetramer in DMPC showed formation of a toroidal
pore after 1 mus (Leveritt et al. 2015). The pore remains stable with a roughly constant radius for the rest of the
simulation. One or two melittin monomers frequently transitioned between transmembrane
and surface states. All four peptides were largely helical. A simulation in a DMPC/DMPG membrane did
not lead to a stable pore, consistent with the experimentally observed lower activity of melittin in
anionic membranes. Thus, a dynamic toroidal
pore seems to account for the transport properties of melittin (Leveritt et al. 2015). Melittin can form small short-lived pores and larger more stable pores (Sun et al. 2015).